Dasatinib induces autophagy in mice with Bcr-Abl-positive leukemia.
Dasatinib induces autophagy in mice with Bcr-Abl-positive leukemia.
复制标题
达沙替尼可诱导 Bcr-Abl 阳性白血病小鼠发生自噬。
DOI：
10.1007/s12185-016-2137-5
复制
发表时间：
2017
期刊：
影响因子：
2.1
通讯作者：
Adachi S.
中科院分区：
文献类型：
--
作者：
Morita M;Nishinaka Y;Kato I;Saida S;Hiramatsu H;Kamikubo Y;Heike T;Nakahata T;Adachi S.
达沙替尼是第二代酪氨酸激酶抑制剂，是治疗 Bcr-Abl 阳性白血病的高效药物。然而，达沙替尼诱导细胞死亡的机制尚不清楚，特别是在体内。自噬是细胞存活和分化所必需的溶酶体降解机制。自噬还可以保护细胞免受药物的影响，包括用于治疗白血病的药物。在这里，我们报告达沙替尼在 Bcr-Abl 阳性白血病细胞系中诱导自噬，并进一步在具有中枢神经系统 (CNS) 浸润的人 Bcr-Abl 阳性白血病免疫缺陷小鼠模型中诱导自噬。在骨髓（BM）和脑脊液（CSF）中诱导自噬。这项研究首次表明自噬诱导是浸润中枢神经系统的白血病细胞细胞死亡的机制之一。因此，自噬可能代表治疗伴有中枢神经系统浸润的 Bcr-Abl 白血病的新治疗靶点。
Dasatinib, a second-generation tyrosine kinase inhibitor, is a highly effective treatment for Bcr-Abl-positive leukemia. However, the mechanism by which dasatinib induces cell death is unclear, particularly in vivo. Autophagy is a lysosomal degradation mechanism essential for cell survival and differentiation. Autophagy also protects cells from the effects of drugs, including those used to treat leukemia. Here, we report that dasatinib induces autophagy in Bcr-Abl-positive leukemia cell lines and further show the induction of autophagy in an immunodeficient mouse model of human Bcr-Abl-positive leukemia with central nervous system (CNS) infiltration. Autophagy was induced in bone marrow (BM) as well as cerebrospinal fluid (CSF). This study is the first to show that autophagy induction is one of the mechanisms underlying cell death in leukemic cells that infiltrate the CNS. Thus, autophagy may represent a novel therapeutic target for the treatment of Bcr-Abl leukemia with CNS infiltration.